Germline mutations in the MEN1 gene encoding menin predispose to endocrine tumors mainly of the parathyroids, anterior pituitary and entero-pancreatic endocrine tissues. We have investigated the molecular basis of this tissue specific tumorigenesis from menin loss in the pathogenesis of tumors of the pancreatic islet -cells (insulinoma). It is possible that the cause of the tissue-specificity is due to menin-mediated regulation of one or more tissue-specific factors such as those that control differentiation during embryogenesis. Therefore, we assessed the effect of menin loss or gain on the expression of factors that are known to control -cell differentiation. We found that the -cell differentiation factor HLXB9 (Mnx-1) is post-transcriptionally upregulated upon menin loss. HLXB9 causes apoptosis in the presence of menin, in MIN6 insulinoma -cells. Thus, dysregulation of HLXB9 predicts a possible mechanism for -cell proliferation in insulinomas resulting from the possible blockade of the pro-apoptotic activity of HLXB9 upon menin loss. These findings advance the understanding of how a ubiquitously expressed protein such as menin controls tissue-specific tumorigenesis in the pancreas. Moreover, our data reveal the mechanisms of action of HLXB9 and its targets in -cells. We also showed that HLXB9 is phosphorylated by the kinase GSK-3, both phospho-HLXB9 and GSK-3 are expressed in mouse and human insulinomas, and GSK-3 inhibitors (such as lithium chloride) reduced cell proliferation and delayed cell cycle progression of mouse insulinoma cell lines. In order to understand the molecular mechanisms by which phospho-HLXB9 promotes tumorigenesis, we have identified interacting proteins and direct target genes of phospho-HLXB9 in insulinoma cells. We found that a survival factor Nono (Non-POU domain-containing octamer binding protein, also known as p54nrb, 54 kDa nuclear RNA binding protein) interacts specifically with the phospho isoform of HLXB9 explaining why phospho-HLXB9 could be pro-oncogenic. Another target that we have identified by anti-phospho-HLXB9 ChIP-Seq is the c-Met inhibitor Cblb, which is downregulated by phospho-HLXB9 that would lead to upregulation of c-Met. Thus our data propose that targeting the HLXB9-NONO interaction and the oncogenic receptor c-MET in insulinomas may be therapeutic. Indeed, insulinomas from the mouse models of menin-loss show activation of the oncogenic c-Met pathway (increased phospho-HLXB9, reduced Cblb and increased c-Met). Further investigations in insulinomas and other pancreatic neuroendocrine tumors will help to explore the relevance of these pathways and the potential of c-Met inhibitor therapy.